Estradiol Gel

The 2022 hormone therapy position statement of The North American Menopause Society concludes that hormone therapy remains the most effective treatment for vasomotor symptoms and the genitourinary syndrome of menopause, and that for women under 60, or within 10 years of menopause onset and without contraindications, the benefit-risk ratio is favourable for treating those symptoms.¹

In the 12-week randomized, double-blind, placebo-controlled registration trial of estradiol gel 0.1 percent, 488 postmenopausal women were evaluated across three once-daily doses of 1.0, 0.5 and 0.25 mg of estradiol, with estimated daily deliveries of 0.027, 0.009 and 0.003 mg, and placebo. All three doses produced statistically significant reductions in the frequency and severity of moderate to severe vasomotor symptoms compared with placebo, maintained through treatment, and all three also improved the objective signs of vulvar and vaginal atrophy, vaginal pH and the percentage of superficial cells.² The FDA-approved labeling describes the same trial in 495 postmenopausal women aged 34 to 89, mean age 54.6, who recorded at least 50 moderate to severe hot flushes per week at baseline; separation from placebo came at week 4 for the two higher doses and week 7 for the lowest, and was statistically significant for all three at week 12.³

A second approved estradiol gel, at 0.06 percent, was tested in a placebo-controlled trial of 145 postmenopausal women aged 29 to 67 randomized to 1.25 g of gel containing 0.75 mg of estradiol or to placebo gel for 12 weeks. At week 12 the mean number of moderate to severe hot flushes per day fell by 7.55 on the gel and by 5.84 on placebo, a difference of 1.71 flushes per day, p equals 0.043, with a wider separation on the daily severity score, p less than 0.001.⁴

A systematic review restricted to double-blind, placebo-controlled randomized trials of transdermal estrogen below the equivalent of 0.05 mg of 17-beta estradiol identified nine trials in postmenopausal women who had at least seven hot flashes a day or 50 a week. Mean daily reductions from baseline were 9.36, 7.91 and 7.07 hot flashes across three descending dose bands against 5.07 on placebo, and eight of the nine trials reported a significant difference from placebo at p less than 0.05.⁵

The Women’s Health Initiative ran two separate randomized, double-blind, placebo-controlled trials, and they did not find the same thing. In 16,608 postmenopausal women aged 50 to 79 with a uterus given oral conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg, hazard ratios over a mean 5.2 years were 1.29 for coronary heart disease, 95 percent confidence interval 1.02 to 1.63, 1.26 for invasive breast cancer, 1.00 to 1.59, 1.41 for stroke, 1.07 to 1.85, and 2.13 for pulmonary embolism, 1.39 to 3.25, which is 7, 8, 8 and 8 excess events per 10,000 person-years, alongside 6 fewer colorectal cancers and 5 fewer hip fractures.⁶ In 10,739 women with a prior hysterectomy given conjugated equine estrogens alone for an average 6.8 years, stroke rose, hazard ratio 1.39, 1.10 to 1.77, or 12 extra strokes per 10,000 person-years; hip fracture fell, 0.61, 0.41 to 0.91; coronary heart disease was unchanged, 0.91, 0.75 to 1.12; and breast cancer was 0.77, 0.59 to 1.01.⁷

A prespecified secondary analysis of both Women’s Health Initiative trials found the coronary result varied with how long a woman had been postmenopausal. At less than 10 years since menopause the hazard ratio for coronary heart disease was 0.76, 95 percent confidence interval 0.50 to 1.16; at 10 to 19 years 1.10, 0.84 to 1.45; at 20 or more years 1.28, 1.03 to 1.58, p for trend 0.02, with absolute excess risks of minus 6, 4 and 17 events per 10,000 person-years. Stroke risk was elevated regardless of timing, hazard ratio 1.32, 1.12 to 1.56.⁸